Project 2 Project Leader: Griffith, Leslie C. Project Summary / Abstract The public health and economic impact of circadian and sleep misalignment had grown enormously with the increasingly global and 24-hour nature of our society, and costs are in the billions. In spite of this, however, we know very little about the mechanisms by which sleep is regulated. This project will provide the first comprehensive look at the function of microRNAs (miRs) in sleep. The dominant model of how the amount of sleep is determined is that the major regulators of sleep are the circadian clock and homeostatic sleep drive. It has become clear in the last few years, however, that other physiological variables can also exert modulatory influences. We have recently completed a screen of a library of miR-sponges and identified specific miRs which appear to be essential for each of these levels of control and we propose to understand the roles of these miRs at the molecular and cellular levels. This project is also part of a more integrated assault on the conserved roles of miRs in plasticity. Sleep and synaptic plasticity have been posited to be intimately related for two reasons. The first is that sleep itself is a daily exercise in rewiring: sensory inputs and motor outputs are suppressed. The second is that one of the most compelling theories of why we sleep is that we need a daily ?resetting? of our circuitry to keep synaptic weights and circuit activity with a linear range to prevent saturation of our information storage capacity. Our work on sleep-regulating miRs will be analyzed in the context of experiments done by the Van Vactor lab on NMJ synaptic plasticity and by the Davis lab on associative learning to give us a glimpse into the more fundamental roles of miRs in regulation of synaptic function. Specific Aims: 1: Determine the complete set of microRNAs which control sleep. 2. Determine how miR190 regulates sleep plasticity. 3. Determine the role of miR92a/b in the regulation of sleep by the clock. 4. Determine the role of let-7 in the hormonal regulation of sleep.